BMAL1 and CLOCK, Two Essential Components of the Circadian Clock, Are Involved in Glucose Homeostasis

PLoS Biol. 2004 Nov;2(11):e377. doi: 10.1371/journal.pbio.0020377. Epub 2004 Nov 2.

Abstract

Circadian timing is generated through a unique series of autoregulatory interactions termed the molecular clock. Behavioral rhythms subject to the molecular clock are well characterized. We demonstrate a role for Bmal1 and Clock in the regulation of glucose homeostasis. Inactivation of the known clock components Bmal1 (Mop3) and Clock suppress the diurnal variation in glucose and triglycerides. Gluconeogenesis is abolished by deletion of Bmal1 and is depressed in Clock mutants, but the counterregulatory response of corticosterone and glucagon to insulin-induced hypoglycaemia is retained. Furthermore, a high-fat diet modulates carbohydrate metabolism by amplifying circadian variation in glucose tolerance and insulin sensitivity, and mutation of Clock restores the chow-fed phenotype. Bmal1 and Clock, genes that function in the core molecular clock, exert profound control over recovery from insulin-induced hypoglycaemia. Furthermore, asynchronous dietary cues may modify glucose homeostasis via their interactions with peripheral molecular clocks.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ARNTL Transcription Factors
  • Analysis of Variance
  • Animal Feed
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / physiology*
  • Body Mass Index
  • CLOCK Proteins
  • Circadian Rhythm
  • Corticosterone / metabolism
  • Diet
  • Gene Deletion
  • Glucagon / metabolism
  • Gluconeogenesis
  • Glucose / metabolism*
  • Glucose Tolerance Test
  • Homeostasis
  • Hypoglycemia / pathology
  • Insulin / metabolism
  • Mice
  • Mice, Transgenic
  • Mutation
  • Phenotype
  • Time Factors
  • Trans-Activators / genetics
  • Trans-Activators / physiology*
  • Triglycerides / metabolism

Substances

  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Insulin
  • Trans-Activators
  • Triglycerides
  • Glucagon
  • CLOCK Proteins
  • Clock protein, mouse
  • Glucose
  • Corticosterone